Domestic researchers have captured the 'hidden stage' of how cell membrane proteins pair for the first time in the world. This discovery breaks the existing theory that proteins bind all at once, revealing that they actually complete their binding through several intermediate steps, like a zipper.
A research team led by Professor Min Duyoung from the Ulsan National Institute of Science and Technology (UNIST) reported on the 8th that they tracked the process of cell membrane proteins pairing in real-time, identifying the intermediate steps involved. The research findings were published in the international journal 'Nature Communications' on Aug. 9.
The membrane surrounding cells is embedded with numerous proteins. These membrane proteins serve as gateways to accept external signals or release signaling substances, and more than 50% of them must pair to function properly.
This study revealed that membrane proteins gradually bind to each other in this process. Proteins do not attach immediately; instead, they engage at specific sites and go through various intermediate steps before ultimately completing a pair. Previously, it was known only that the two membrane proteins would approach and bind at once.
The research team uncovered this using a new analytical method called 'single-molecule tweezers' for membrane protein interactions. This method allows researchers to capture and pull both proteins with a sort of tweezer while recording in real-time how the binding progresses and breaks.
This was further validated by additional experiments. The researchers interfered with the binding by inserting short peptide fragments between the membrane proteins. As a result, the proteins' binding stopped at the intermediate stage. Just like if the middle tooth of a zipper breaks, it wouldn't close all the way; if certain stages are blocked, the binding of membrane proteins will not be completed.
Professor Min noted, 'The fact that membrane proteins sequentially bind through intermediate stages is a significant turning point in understanding protein interactions. The principle of inhibiting this membrane protein binding is also applied in the breast cancer drug 'Perjeta.' By uncovering the hidden stages of binding and applying selective blocking methods, it will be possible to design more effective new drugs.'
Professor Min also expressed hope that 'the single-molecule tweezers analytical method used in this study could be utilized to precisely elucidate the membrane protein binding processes that are medically important.'
References
Nature Communications (2025), DOI: https://doi.org/10.1038/s41467-025-62852-1